The present invention relates to the use of a combination of an angiotensin converting enzyme inhibitor (CEI) and of a diuretic for producing pharmaceutical compositions intended for the treatment of arteriolo-capillary microcirculatory disorders.
It is known that the majority of degenerative vascular diseases, for example arterial hypertension (N. M. Kaplan, xe2x80x9cMicrovascular Rarefactionxe2x80x9d, Clinical Hypertension, 6th Ed., Baltimore, Wilkinson and Wilkins, 1994, 86; A. S. Greene et al., xe2x80x9cMicrovascular rarefaction and tissue vascular resistance in hypertensionxe2x80x9d, Am. J. Physiol., 1989, 256 (Heart Circ. Physiol., 25), H 126-H 31; A. S. Izzard et al., xe2x80x9cHypertension and the vasculature: arterioles and the myogenic responsexe2x80x9d, J. Hypertens., 1995, 13, 1-4; A. M. Heagerty et al., xe2x80x9cSmall artery structure in hypertensionxe2x80x9d, Hypertension, 1993, 21, 391-7), but also vascular complications of certain metabolic diseases, for example diabetes mellitus (G. Reach et al., xe2x80x9cCauses et mxc3xa9canismes de la microangiopathie et de la neuropathiexe2x80x94xe2x80x9cL""hypothxc3xa8se glucosexe2x80x9d et ses implications [Causes and mechanisms of microangiopathy and neuropathyxe2x80x94xe2x80x9cThe glucose hypothesisxe2x80x9d and its implications]xe2x80x9d, in: G. Tchobroutsky, G. Slama, R. Assan, P. Freychet, Paris: Pradel, 1990, 448-57), or certain dyslipidemias (J. F. Toole, xe2x80x9cAtherosclerosisxe2x80x9d, Cerebrovascular Disorders, New York, Raven Press, 1984, 199-213) are accompanied by detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation (J. C. M. L. Le Noble et al., xe2x80x9cA functional morphometric study of the cremaster muscle microcirculation in young spontaneously hypertensive ratsxe2x80x9d, J. Hypertens., 1990, 8,741-8; I. I. H. Chen et al., xe2x80x9cMicrovascular rarefaction in spontaneously hypertensive rat cremaster musclexe2x80x9d, Am. J. Physiol., 1981, 241, H 306-10).
The detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation can take different forms, such as, for example:
an arteriolo-capillary rarefaction (P. Gasser, xe2x80x9cNailfold microcirculation in normotensive and essential hypertensive subjects as assessed by video-microscopyxe2x80x9d, J. Hypertens., 1992, 1, 83-6),
a lack of arteriolo-capillary recruitment (B. W. Zweifach, xe2x80x9cMicropressure-flow relationships in a skeletal muscle of spontaneously hypertensive ratsxe2x80x9d, Hypertension, 1981, 3, 601-14),
and, more generally, poor adjustment of the distribution of the blood in the tissues to metabolic requirements, any detrimental change capable of inducing or perpetuating a tissue hypoperfusion or an ischemia, absolute or relative (E. Vicaut, xe2x80x9cHypertension and the microcirculation: a brief overview of experimental studiesxe2x80x9d, J. Hypertens., 1992, 10, suppl. 5, S59-S68).
It is also known that the detrimental anatomical and/or functional changes in the arteriolo-capillary microcirculation described above can precede, for example, the rise in pressure values in arterial hypertension, creating for some a true vicious circle (A. J. Zweifler et al., xe2x80x9cDiminished finger pulse in borderline hypertension: evidence for early structural vascular abnormalityxe2x80x9d, Am. Heart J., 1982, 104, 812-15; J. M. Sullivan et al., xe2x80x9cAttenuation of the microcirculation in young patients with high-output borderline hypertensionxe2x80x9d, Hypertension, 1983, 5, 844-51).
Finally, it is known that a great many factors are involved simultaneously in the regulation of general hemodynamics (outputs, resistances, pressures, and the like) and in the regulation, or rather adjustment, of the distribution of blood in the tissues according to the context (hierarchization depending on the nature of the organs, and the like) and the metabolic requirements of the moment (M. J. Mulvany, xe2x80x9cThe structure of the resistance vasculature in essential hypertensionxe2x80x9d, J. Hypertens., 1987, 5, 129:H; H. A. J. Struijker-Boudier et al., xe2x80x9cThe microcirculation and hypertensionxe2x80x9d, J. Hypertens., 1992, 10 (suppl. 7), S147-S156).
A great many vasoactive substances have been identified, with very particular interest in recent years in, by way of example, substances originating from or having an effect on smooth muscle fibers and the vascular endothelium (S. Laurent et al., xe2x80x9cPhysiopathologie et pharmacologie du remodelage artxc3xa9riel dans l""hypertension artxc3xa9rielle [Physiopathology and pharmacology of arterial remodeling in arterial hypertension]xe2x80x9d, the letter from the pharmacologist, 1997, 11, 146-54; Taddei et al., xe2x80x9cHypertension causes prematurate [sic] aging of endothelial function in humansxe2x80x9d, Hypertension, 1997, 29, 736-43).
The complexity of these different regulations, the number of factors involved and their interactivity, better understood today, have led us to provide the combination of several medicaments, directly or indirectly vasoactive, for both preventing and treating:
on the one hand, the clinical attack, for example arterial hypertension, when the rise in pressure values reaches, or indeed exceeds, the standards recommended by the international scientific community;
on the other hand, its repercussions on tissue perfusion in the context of macro/microcirculatory disorders which, it is known, can precede, maintain and aggravate the clinical entity described above by way of example (arterial hypertension but also, for example, vascular complications of certain metabolic diseases, and the like) (H. A. J. Struijker-Boudier et al., xe2x80x9cAssessment of the microcirculation in cardiovascular diseasexe2x80x9d, Clin. Sci., 1996, 91, 131-9).
The actions of different vasoactive substances can thus usefully complement one another and provide an improved therapeutic effect in the basic treatment of degenerative vascular diseases, or indeed in the prevention of the incidents and accidents which they induce.
It is also known that some CEIs have a beneficial effect on arteriolar or coronary microcirculation but at no time has a beneficial effect on the functional unit represented by an arteriola and the adjacent capillaries been demonstrated in the literature.
It has now been shown, which is the subject of the present invention, that the combination of a CEI with a diuretic, in addition to the known properties of this combination, made it possible, surprisingly, to correct microcirculatory disorders at both the arteriolar and capillary level, whereas no property of this nature had ever been described or claimed in prior publications or patents relating to combinations, in particular of CEI and of diuretics, to CEIs or to diuretics.
The novelty of this type of combination of vasoactive agents lies in addition in the fact, in particular, that each of the constituents of the combination is generally used at low doses, generally lower than those used in each of their first indications.
The usefulness of this type of combination thus lies in the production of pharmaceutical compositions of use in the treatment of arteriolo-capillary micro-circulatory disorders. These compositions can thus be used in all pathologies where microcirculatory disorders are involved, such as, for example, degenerative vascular diseases, arterial hypertension, cardiac insufficiency, cerebral ischemia, heart attacks, arteritis of the lower limbs, the prevention and treatment of cardiovascular complications of type-II diabetes, retinopathies, nephropathies, and the like, as main or secondary treatment.
The CEIs which can be used in these compositions are, without implied limitation: Perindopril, Captopril, Enalapril, Lisinopril, Delapril, Fosinopril, Quinapril, Ramipril, Spirapril, Imidapril, Trandolapril, Benazepril, Cilazapril and Temocapril, and their addition salts with a pharmaceutically acceptable acid orbase.
The preferred CEIs are Perindopril, Captopril, Enalapril, Lisinopril, Benazapril, Quinapril and Delapril and their salts and more particularly Perindopril and its salts.
The diuretics which can be used in these compositions are, without implied limitation: Indapamide, Hydrochlorothiazide, Furosemide, Altizide, Trichlormethiazide, Triflumethazide, Bemetizide, Cyclothiazide, Methylclothiazide, Azosemide, Chlorothiazide, Butizide, Bendrofluazide, Cyclopenthiazide, Benzchlortriazide, Polythiazide, Hydroflumethiazide, Benzthiazide, Ethiazide, Penflutazide, Clopamide, Cicletanide or Piretanide, and their addition salts with a pharmaceutically acceptable acid or base.
The preferred diuretics are Indapamide and Hydrochlorothiazide and their salts and more particularly Indapamide and its salts.
The invention thus more preferably relates to the use of a combination of the converting enzyme inhibitor Perindopril or one of its addition salts with a pharmaceutically acceptable base and of the diuretic Indapamide in order to obtain pharmaceutical compositions intended for the treatment of arteriolo-capillary microcirculatory disorders.
The pharmaceutical compositions according to the invention will be presented in pharmaceutical forms suitable for administration by the oral, parenteral and in particular intravenous, per- or transcutaneous, nasal, rectal, perlingual, ocular or respiratory route and more specifically tablets, sublingual tablets, capsules, including hard gelatin capsules, glossettes, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels, and the like.
The preferred administration route is the oral route and the corresponding pharmaceutical compositions which allow the instantaneous or delayed release of the active principles.
Tablets are the preferred pharmaceutical compositions.
In the pharmaceutical compositions according to the invention, the amounts of CEI and of diuretic are adjusted to the nature of these active principles and their relative proportions thus vary with the active principles.
When the CEI is Perindopril in the tert-butylamine salt form and when the diuretic is Indapamide, these proportions are respectively between 65 and 85% and between 35 and 15% of the total mass of the active principles and preferably between 70 and 80% for the CEI and between 30 and 20% for the diuretic.
The preferred percentages for this combination are 76% of tert-butylamine salt of Perindopril and 24% of Indapamide.
The compositions according to the invention, in addition to the active principles, contain one or more pharmaceutically acceptable vehicles or excipients.
Mention may be made, among pharmaceutically acceptable excipients, without implied limitation, of binders, diluents, disintegrating agents, stabilizing agents, preservatives, lubricants, fragrances, flavoring agents or sweeteners.
The posology varies according to the age and weight of the patient, the administration route or the nature of the therapeutic indication and of the associated treatments. It ranges between 1 and 50 mg according to the nature of the CEI and between 0.5 and 25 mg according to the nature of the diuretic, taken one or more times per 24 hours.